Ribosomal proteins and human diseases: molecular mechanisms and targeted therapy

Kang, Jian; Brajanovski, Natalie; Chan, Keefe T.; Xuan, Jiachen; Pearson, Richard B.; Sanij, Elaine

doi:10.1038/s41392-021-00728-8

Cited by 195 publications

(179 citation statements)

References 360 publications

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“…Interestingly, a T-cell specific loss of Rps26 did not affect overall translation rates, but rather increased p53 signalling, and thus resulted in cell death (84). A significant increase of p53 expression was also observed in HeLa cells upon knock down of 24 out of 80 ribosomal proteins and has been attributed to the accumulation of free ribosomal proteins in the nucleus (85,86). This decreased viability will thus impede the study of at least a subset of ribosomal proteins in T cells.…”

Section: Discussionmentioning

confidence: 99%

RNA-Binding Protein Expression Alters Upon Differentiation of Human B Cells and T Cells

2021

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B cells and T cells are key players in the defence against infections and malignancies. To exert their function, B cells and T cells differentiate into effector and memory cells. Tight regulation of these differentiation processes is key to prevent their malfunction, which can result in life-threatening disease. Lymphocyte differentiation relies on the appropriate timing and dosage of regulatory molecules, and post-transcriptional gene regulation (PTR) is a key player herein. PTR includes the regulation through RNA-binding proteins (RBPs), which control the fate of RNA and its translation into proteins. To date, a comprehensive overview of the RBP expression throughout lymphocyte differentiation is lacking. Using transcriptome and proteome analyses, we here catalogued the RBP expression for human B cells and T cells. We observed that even though the overall RBP expression is conserved, the relative RBP expression is distinct between B cells and T cells. Differentiation into effector and memory cells alters the RBP expression, resulting into preferential expression of different classes of RBPs. For instance, whereas naive T cells express high levels of translation-regulating RBPs, effector T cells preferentially express RBPs that modulate mRNA stability. Lastly, we found that cytotoxic CD8+ and CD4+ T cells express a common RBP repertoire. Combined, our study reveals a cell type-specific and differentiation-dependent RBP expression landscape in human lymphocytes, which will help unravel the role of RBPs in lymphocyte function.

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Section: Discussionmentioning

confidence: 99%

RNA-Binding Protein Expression Alters Upon Differentiation of Human B Cells and T Cells

2021

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“…Ribosome biogenesis and protein synthesis are fundamental rate-limiting steps for cell growth and proliferation [44]. In eukaryotes, ribosome assembly is a rate-limiting step in ribosomal biogenesis.…”

Section: Analysis Of Candidate Degs Involved In Ribosome Biosynthesis...mentioning

confidence: 99%

Transcriptome Profiling Revealed Basis for Growth Heterosis in Hybrid Tilapia (Oreochromis niloticus ♀ × O. aureus ♂)

Zhu

Zou

et al. 2022

Fishes

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Hybrid tilapia were produced from hybridization of Nile tilapia (Oreochromis niloticus) and blue tilapia (O. aureus). Comparative transcriptome analysis was carried out on the liver of hybrid tilapia and their parents by RNA sequencing. A total of 2319 differentially expressed genes (DEGs) were identified. Trend co-expression analysis showed that non-additive gene expression accounted for 67.1% of all DEGs. Gene Ontology and KEGG enrichment analyses classified the respective DEGs. Gene functional enrichment analysis indicated that most up-regulated genes, such as FASN, ACSL1, ACSL3, ACSL6, ACACA, ELOVL6, G6PD, ENO1, GATM, and ME3, were involved in metabolism, including fatty acid biosynthesis, unsaturated fatty acid biosynthesis, glycolysis, pentose phosphate pathway, amino acid metabolism, pyruvate metabolism, and the tricarboxylic acid cycle. The expression levels of a gene related to ribosomal biosynthesis in eukaryotes, GSH-Px, and those associated with heat shock proteins (HSPs), such as HSPA5 and HSP70, were significantly down-regulated compared with the parent tilapia lineages. The results revealed that the metabolic pathway in hybrid tilapia was up-regulated, with significantly improved fatty acid metabolism and carbon metabolism, whereas ribosome biosynthesis in eukaryotes and basal defense response were significantly down-regulated. These findings provide new insights into our understanding of growth heterosis in hybrid tilapia.

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“…Defects in ribosome biogenesis can lead to congenital diseases called ribosomopathies ( Narla and Ebert, 2010 ; Farley-Barnes et al, 2019 ; Kang et al, 2021 ). Ribosomopathies such as the Diamond Blackfan anemia (DBA) or the Shwachman Diamond syndrome include various clinical manifestations.…”

Section: Introductionmentioning

confidence: 99%

The Ribosomal Protein L5 Functions During Xenopus Anterior Development Through Apoptotic Pathways

Schreiner

Kernl

Dietmann

et al. 2022

Front. Cell Dev. Biol.

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Ribosomal biogenesis is a fundamental process necessary for cell growth and division. Ribosomal protein L5 (Rpl5) is part of the large ribosomal subunit. Mutations in this protein have been associated with the congenital disease Diamond Blackfan anemia (DBA), a so called ribosomopathy. Despite of the ubiquitous need of ribosomes, clinical manifestations of DBA include tissue-specific symptoms, e.g., craniofacial malformations, eye abnormalities, skin pigmentation failure, cardiac defects or liver cirrhosis. Here, we made use of the vertebrate model organism Xenopus laevis and showed a specific expression of rpl5 in the developing anterior tissue correlating with tissues affected in ribosomopathies. Upon Rpl5 knockdown using an antisense-based morpholino oligonucleotide approach, we showed different phenotypes affecting anterior tissue, i.e., defective cranial cartilage, malformed eyes, and microcephaly. Hence, the observed phenotypes in Xenopus laevis resemble the clinical manifestations of DBA. Analyses of the underlying molecular basis revealed that the expression of several marker genes of neural crest, eye, and brain are decreased during induction and differentiation of the respective tissue. Furthermore, Rpl5 knockdown led to decreased cell proliferation and increased cell apoptosis during early embryogenesis. Investigating the molecular mechanisms underlying Rpl5 function revealed a more than additive effect between either loss of function of Rpl5 and loss of function of c-Myc or loss of function of Rpl5 and gain of function of Tp53, suggesting a common signaling pathway of these proteins. The co-injection of the apoptosis blocking molecule Bcl2 resulted in a partial rescue of the eye phenotype, supporting the hypothesis that apoptosis is one main reason for the phenotypes occurring upon Rpl5 knockdown. With this study, we are able to shed more light on the still poorly understood molecular background of ribosomopathies.

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Ribosomal proteins and human diseases: molecular mechanisms and targeted therapy

Cited by 195 publications

References 360 publications

RNA-Binding Protein Expression Alters Upon Differentiation of Human B Cells and T Cells

RNA-Binding Protein Expression Alters Upon Differentiation of Human B Cells and T Cells

Transcriptome Profiling Revealed Basis for Growth Heterosis in Hybrid Tilapia (Oreochromis niloticus ♀ × O. aureus ♂)

The Ribosomal Protein L5 Functions During Xenopus Anterior Development Through Apoptotic Pathways

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